The present invention relates to new ester derivatives of deoxyfluorouridine of the general formula: ##STR2## wherein R and R', which may be identical or different, each stands for a hydrogen or halogen atom or methyl group and n stands for 3 or 4. The present invention further relates to a process for the preparation of the ester derivatives and anti-tumor agents containing the ester derivatives as an active ingredient.
2'-Deoxy-5-fluorouridine (referred to hereinafter as FUDR) has been used as an anti-tumor agent but this compound is exceptionally high in toxicity for use as a medication and thus has a narrow safety region. In addition, this compound has considerable limitations in actual therapeutic applications since the mode of administering this compound is limited only to intraarterial injection, or in other words, this compound cannot be administered orally [Physicians' Desk Reference, p. 1387 (1978)]. 2'-Deoxy-3',5'-di-O-acetyl-5-fluorouridine (referred to hereinafter simply as acetyl-FUDR) is also known as one of the FUDR derivatives. However, this compound is evaluated as being almost equivalent in anti-tumor activity to FUDR and rather poor in effectiveness [Biochem. Pharmacology, 14, 1605 et seq., (1965); Cancer Research, 23, 420 et seq. (1963)].
3',5'-Dialkyl esters of FUDR are also reported as derivatives of FUDR [Biochem. Pharmacology, 14, 1605-1619 (1965), ibid. 15, 627-644 (1966)]. However, no compound was found which was satisfactory with respect to anti-tumor activity and toxicity levels. It was reported by C. Heidelberger et al that the nitrogen atom in the 3-position of the pyrimidine nucleus of FUDR should not be substituted for anti-tumor activity [Cancer Research, 30, 1555-6, (1970)]. It has been found unexpectedly that compounds having a specific aroyl group as a substituent on the nitrogen atom in the 3-position of the pyrimidine nucleus of FUDR, for example, 3-(3-methylbenzoyl)-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine etc., have a superior anti-tumor activity (Japanese unexamined patent publication No. 35057/1980). Some derivatives substituted on the 3-position of the pyrimidine of FUDR, for example, 3-(3-methylbenzoyl)-2'-deoxy-5-fluorouridine etc., are also known (Japanese unexamined patent publication No. 163586/1979). However, improvement in anti-tumor activity in such FUDR compounds is desirable.
Recently, reported FUDR and acetyl-FUDR derivatives have included compounds wherein the hydrogen atom bonded to the nitrogen atom at the 3-position on the uracil ring is substituted by a specific aroyl group (UK Patent Appln. No. 2,025,401 published on Jan. 23, 1980 and European Patent Appln. No. 9,882 published on Apr. 16, 1980). However, further enhancement in anti-tumor activity is desired also in these compounds. Thus, there is a great demand for developing new FUDR derivatives which possess strong anti-tumor activity with weak toxicity and are suitable for oral administration without the necessity of troublesome intraarterial or intravenous injection.